PROJECT SUMMARY Alterations in the epigenome have been associated with changes in cellular identity and have emerged as important drivers in human cancer. In melanoma, we have shown that overexpression of SETDB1 and SUV39H1, two histone 3 lysine 9 methyltransferases (H3K9 HMTs), accelerate melanoma formation in zebrafish and are also amplified in human cases. Recently, our lab has used the histone 3 lysine-to-methionine mutation at K9 (H3.3K9M) to interrogate the consequences of H3K9 HMT loss of function. Remarkably, we find that expression of H3.3K9M suppresses tumor onset. Because histone methylation is known to play a critical role in proper maintenance of cellular identity, we hypothesize that loss of H3K9 HMT activity suppresses melanoma through inhibition of the progenitor phenotype, which has been shown to promote melanomagenesis. We propose using both zebrafish and human melanoma cell lines to identify the mechanisms through which loss of H3K9 HMT activity suppresses melanoma formation.